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  • Review Article
  • Published:

Regulating antigen-receptor gene assembly

Nature Reviews Immunology volume 3, pages 890–899 (2003)Cite this article

Key Points

  • V(D)J recombination depends on the lymphoid-specific recombinase-activating gene 1 (RAG1) and RAG2 proteins, which recognize conserved recombination signal sequences (RSSs) that flank all rearranging gene segments and introduce double-stranded DNA (dsDNA) breaks. Proteins of the dsDNA-break-repair machinery expressed by all cells then collaborate with the RAG proteins to form recombinant molecules that encode the variable exons of immunoglobulin and T-cell receptor (TCR) genes.

  • V(D)J recombination is regulated in three ways — lineage specificity (immunoglobulin genes rearrange fully in B cells and TCR genes rearrange in T cells), order (immunoglobulin heavy chain rearranges before immunoglobulin light chain, TCRβ rearranges before TCRα), and allelic exclusion (an individual B or T cell expresses only one functional rearrangement at each receptor locus).

  • The RAG1 and RAG2 are physically linked in the genome and are convergently transcribed. Various unusual structural features of the RAG locus have led to the suggestion that the V(D)J recombinase evolved from a primitive transposable element system.

  • RAG1 and RAG2 transcription are coordinately regulated by multiple conserved, lineage-specific cis-acting DNA sequences located 5′ of RAG2. Cell-cycle-associated protein degradation also has an important role in regulating recombinase activity.

  • As all V(D)J recombination events involve a common recombinase (RAG and DNA-break-repair proteins) that recognize conserved RSSs, it was proposed that the regulation of recombination depends on aspects of chromatin structure that determine the accessibility of individual RSSs in vivo. Both in vivo and in vitro, observations strongly support what has become known as the 'accessibility hypothesis'.

  • Unrearranged gene segments are transcribed before or coincident with their activation for rearrangement. The transcriptional enhancers and promoters that regulate these germline transcripts are crucial for establishing chromatin structures that are permissive for V(D)J recombination.

  • Assembly of immunoglobulin and TCR loci into chromatin containing various post-translational histone modifications correlates with active or inactive V(D)J recombination.

  • Allelic exclusion requires two types of mechanism; one that prevents the near-simultaneous rearrangement of allelic loci and another that involves feedback regulation by the product of a successfully rearranged allele.

Abstract

The genes encoding antigen receptors are unique because of their high diversity and their assembly in developing lymphocytes from gene segments through a series of site-specific DNA recombination reactions known as V(D)J rearrangement. This review focuses on our understanding of how recombination of immunoglobulin and T-cell receptor gene segments is tightly regulated despite being catalysed by a common lymphoid recombinase, which recognizes a widely distributed conserved recombination signal sequence. Probable mechanisms involve precise expression of the lymphoid-restricted recombination-activating genes RAG1 and RAG2, and developmentally regulated epigenetic alterations in template accessibility, which are targeted by transcriptional regulatory elements and involve chromatin-modifying enzymes.

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Figure 1: A schematic diagram of the mouse immunoglobulin heavy-chain (IgH) locus showing the positions of the VH, DH and JH gene segments and the IgH intronic enhancer.
Figure 2: Regulation of V(D)J recombinase activity during lymphocyte development.
Figure 3: The recombinase-activating gene locus.
Figure 4: A model for the mechanisms of allelic exclusion of immunoglobulin gene expression.

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Acknowledgements

I would like to acknowledge my students and fellows, past and present, who have contributed to advancing our knowledge of V(D)J recombination. Work in my lab is funded by the National Institutes of Health and the Arthritis Foundation.

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  1. Department of Molecular and Cell Biology, University of California, Berkeley, 94720, California, USA

    Mark S. Schlissel

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DATABASES

LocusLink

C/EBP

EBF

EZH2

GATA3

IL-7R

LEF1

LYF1

MYB

NF-Y

PAX5

RAG1

RAG2

RUNX1

SP1

STAT5

Further information

Mark Schlissel's laboratory

Glossary

RECOMBINATION SIGNAL SEQUENCES

(RSSs). Short, conserved DNA sequences that flank all rearranging gene segments and serve as the recognition elements for the recombinase machinery.

POSITIVE SELECTION

Developing T cells are selected for survival and developmental progression based on the avidity of interaction between their T-cell receptors and the ligands expressed by the thymic microenvironment.

FOOTPRINTING ASSAYS

Assays that precisely map DNA–protein interactions by taking advantage of the fact that DNA sequences that are specifically complexed with protein are differentially susceptible to cleavage by nucleases or chemical modifying agents.

DNASE HYPERSENSITIVITY

A technique that allows the location of sites of gene-regulatory sequences because of their increased susceptibility to nucleases within nuclear structure.

CORE RAG1 AND RAG2

The minimal domains of recombinase-activating gene 1 (RAG1) and RAG2 that can activate the rearrangement of a reporter construct. Unlike the full-length proteins, the core domains are soluble and have been used for all biochemical analysis of this reaction.

HISTONE CODE

The concept that site-specific post-translational modification of histones might function to regulate gene activity precisely; the code is determined by which amino acids are acetylated, methylated or phosphorylated.

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Schlissel, M. Regulating antigen-receptor gene assembly. Nat Rev Immunol 3, 890–899 (2003). https://doi.org/10.1038/nri1225

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